Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia.

In an attempt to improve the complete remission (CR) rates and to prolong the remission duration especially in elderly patients > 50 years of age, we have used a combination chemotherapy of idarubicin (10 mg/m2 IV x 3 days), cytarabine (AraC, 100 mg/m2 CIVI x 7d), and etoposide (100 mg/m2 x 5 days) in combination with granulocyte colony-stimulating factor (G-CSF) priming [5 mg/kg SQ day 1 until absolute neutrophil count (ANC) recovery] for remission induction. Responding patients received two consolidation courses of idarubicin, AraC, and etoposide, followed by a late consolidation course of intermediate-dose AraC (600 mg/m2 IV every 12 h x 5 days) and amsacrine (60 mg/m2 IV x 5 days). A total of 112 patients (57 male/55 female) with a median age of 58 years (range: 22-75) have been entered and are evaluable for response: 19 refractory anemia with excess of blast cells in transformation (RAEB-T), 84 acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS), and 9 secondary AML after chemotherapy/radiotherapy. The overall CR rate was 62%, partial remission (PR) rate 10%, treatment failure 16%, and early death rate 12%. The CR rate was higher in patients < or = 60 years (68 vs 55%), mainly due to a lower early death rate (5 vs 21%, p<0.001). After a median follow-up of 58 months, the median overall survival is 14.5% and median duration of relapse-free survival 8 months. After 60 months, the probability of CR patients to still be in CR and alive is 16% (20% in patients < or = 60 years and 13% in patients >60 years), while the probability of overall survival is 12% (15% in patients < or = 60 years and 9% in patients > 60 years). Compared to our previous trial (AML-MDS Study 01-92) which was done with identical chemotherapy but no G-CSF priming in 110 patients with RAEB-T, AML after MDS, or secondary AML (identical median age, age range, and distribution of subtypes), the CR rate in all patients, as well as CR rate, overall survival, and relapse-free survival in patients > 60 years have significantly been improved. Thus, intensive chemotherapy with G-CSF priming is both well tolerated and highly effective for remission induction in these high-risk patients.

Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study.

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.

Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed.

PURPOSE: We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program. PATIENTS AND METHODS: Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks. RESULTS: Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H-related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred. CONCLUSION: Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.

Sex differences in the renal transforming growth factor-beta 1 system after puberty.

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in many progressive kidney diseases. The present study examines this growth factor during the pubertal and early adult periods. Mixed-sex Munich-Wistar rat kidneys were obtained on selected days of life from birth through 6 months of age. A survey of the TGF-beta 1 system was performed, and then a second experiment focused on cortex and medulla from both sexes at 6 weeks and 16 weeks of age. Reverse transcription polymerase chain reaction for TGF-beta 1 and TGF-beta inducible gene H3 (beta IG-H3) was performed. Active and total levels of protein for TGF-beta 1 were isolated from tissue. Active levels of TGF-beta 1 were somewhat lower in older than in younger animals, without sex differences. beta IG-H3 levels were similar. At 16 weeks females had levels of total growth factor approximately threefold greater than males, while adult males appeared to activate the growth factor much more efficiently. These findings suggest that activation of TGF-beta 1 becomes more efficient following puberty in the male rat, while females appear to have reduced activation efficiency compensated by increased total growth factor. These differences may help explain the deterioration at puberty and sexual dimorphism noted with some progressive nephropathies.

Streptozocin diabetes elevates all isoforms of TGF-beta in the rat kidney.

Transforming growth factor beta (TGF-beta) is a major promoter of diabetic nephropathy. While TGF-beta1 is the most abundant renal isoform, types 2 and 3 are present as well and have identical in vitro effects. Whole kidney extracts were studied 2 weeks after induction of streptozocin diabetes and in control rats. Mean glomerular area was 25% greater in the diabetic animals. TGF-beta1 showed a 2-fold increase in message with a 3-fold increase in protein. TGF-beta2 mRNA increased approximately 6% while its protein doubled. TGF-beta-message increased by 25%, producing a 35% increase in its protein. TGF-beta-inducible gene H3 mRNA was increased 35% in the diabetic animals, consistent with increased activity of this growth factor. All isoforms of TGF-beta are increased in the diabetic rat kidney. Future studies need to address the specific role that each isoform plays in diabetic nephropathy as well as the impact of therapies on each isoform.

Puberty permits increased expression of renal transforming growth factor-beta1 in experimental diabetes.

Prepubertal years of diabetes mellitus are relatively protected from clinical manifestations of nephropathy. Transforming growth factor-beta1 (TGF-beta1) is a major mediator of diabetic kidney disease. Its renal expression, translation, and activation change with sexual maturation in the normal rat. The role of TGF-beta1 in postpubertal susceptibility to diabetic renal hypertrophy was addressed in the present study. Male Sprague- Dawley rats were given streptozocin at 4 weeks of age (weanling) or 14 weeks of age (mature) and treated with insulin to maintain blood glucose levels between 300 and 500 mg/dl. Nondiabetic controls received saline. After 6 weeks with ad libitum food and water, kidneys were snap-frozen for measurement of TGF-beta1 protein and mRNA. As in previous studies, diabetic renal hypertrophy was blunted in weanling animals compared with mature rats. Message for TGF-beta1 was not significantly increased in weanling animals [102 (9)% [mean (SEM)] in nondiabetic controls versus 117 (10)% in diabetic rats; P=0.91], while it was significantly increased in mature diabetic animals [100 (7)% vs. 146 (11)%; P=0.01]. Immunohistochemistry revealed focal increases in glomerular staining in mature but not weanling diabetic rats. Differences in the control of the renal TGF-beta system may explain the permissive role of puberty in the manifestations of diabetic kidney disease.

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML).

Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged 60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high- or low-dose IL-2. Patients aged up to 55 years with an HLA-identical sibling donor were eligible for allogeneic bone marrow transplantation. The median relapse-free survival was 12.5 months, with a probability of ongoing CR at 6.5 years of 19%. Overall survival of all patients was 8 months, and 21 months for the CR patients. Median survival was significantly longer among patients aged

Treatment of Adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL).

The German Multicenter Study Group for Adult Acute Lymphoblastic leukemia (GMALL) has conducted 5 consecutive trials with more than 3000 patients since 1981. This article provides an overview on aims, treatment concepts, and results of these studies. It includes brief summaries on the development of prognostic models within the GMALL group and on approaches for prophylaxis of CNS relapse, and it summarizes specific treatment concepts for mature B-lineage acute lymphocytic leukemia.

[Colony stimulating factors in polychemotherapy of testicular tumors. A comparison between G-CSF and GM-CSF]. / Koloniestimulierende Faktoren bei der Polychemotherapie von Hodentumoren. Ein Vergleich zwischen G-CSF und GM-CSF.

Colony-stimulating factors (CSF) are frequently used in cases of cytostatic therapy of patients with testicular cancer assuming that they support hematopoietic recovery and, thus, shorten duration of neutropenia as well as reduce infections. Currently, G-CSF and GM-CSF are clinically used. In the present study efficacy and toxicity of these two drugs were investigated and compared in patients with testicular cancer treated by standard chemotherapy. Studying 83 chemotherapy cycles applied to 31 patients with advanced germ cell tumors the effectivity and the side effects of the two CSF were examined by questioning, clinical evaluation, and blood chemistry studies. G-CSF (480 micrograms subcutaneously (s.c.)) were used in 55 and GM-CSF (400 micrograms s.c.) in 28 chemotherapeutic cycles. The indications consisted in the treatment of leukocytopenia on the one hand and in the prophylaxis in subsequent cycles on the other hand. No difference between the two CSF could be found either with regard to postponement of the next cycle (G-CSF: 6.8 vs. GM-CSF: 7.3 days), or to the number of injections per cycle (G-CSF: 8 vs. GM-CSF: 12.5), or to the leukocyte (G-CSF: 2.1 vs. GM-CSF: 1.6 x 10(3)/microliter) or platelet nadir (G-CSF: 0.5 vs. GM-CSF: 0.5 x 10(5)/microliter; mean values of all cycles, respectively). Both CSF did not seem to influence the production of platelets. However, a difference between the two CSF was demonstrated with respect to the toxicity. Frequency (G-CSF: 38.5% vs. GM-CSF: 69.3%) as well as intensity of side effects causing a change of the drug (G-CSF: n = 1 vs. GM-CSF: n = 7) were lower in the case of G-CSF. In conclusion, these data demonstrate no difference was seen between G-CSF and GM-CSF with respect to the efficacy in patients with testicular cancer treated by standard chemotherapy. However, the use of G-CSF seems to be associated with lower toxicity.

[Radical prostatectomy as primary monotherapy in capsule penetrating prostatic carcinoma. 15 years outcome]. / Radikale Prostatektomie als primäre Monotherapie bei kapselüberschreitendem Prostatakarzinom. 15-Jahres-Ergebnisse.

Twenty-five patients with locally advanced prostate cancer (stage pT3pN0) underwent pelvic lymphadenectomy and radical prostatectomy and were followed up thereafter for at least 15 years. No hormonal treatment was given prior to tumor progression. Overall and disease-free 15-year survival rates were observed to be 44 and 24%, respectively. These data suggest that a cure from prostate cancer by radical prostatectomy can be expected in a quarter of patients with capsular penetration. From our results, no justification can be derived to exclude radical prostatectomy from the spectrum of treatment options for patients with capsular penetration of prostate cancer. More detailed analysis of the results depending on the local extent of the tumor and histological grade revealed distinct differences with respect to the risk of progression. Histological grade was the single most predictive parameter of progression. Out of all subgroups of patients with capsular penetration of prostate cancer, those with a poorly differentiated tumor showed the shortest progression-free interval after surgery, the highest level of overall progression and the largest proportion of tumor-related deaths. By contrast, the prognosis was only slightly influenced by the presence or absence of seminal vesicle involvement. The role of adjuvant treatment after radical prostatectomy for patients with stage pT3pN0 prostate cancer or for subgroups of them remains to be determined within the scope of prospective randomized trials.

First astronomical detection of the cumulene carbon chain molecule H2C6 in TMC-1.

The cumulene carbenes are important components of hydrocarbon chemistry in low-mass star-forming cores. Here we report the first astronomical detection of the long-chain cumulene carbene H2C6 in the interstellar cloud TMC-1, from observations of two of its rotational transitions: J(K,K') = 7(1,7) --> 6(1,6) at 18.8 GHz and 8(1,8) --> 7(1,7) at 21.5 GHz, using NASA's Deep Space Network 70 m antenna at Goldstone, California. In addition we also observed the shorter cumulene carbene H2C4 at the same position. The fractional abundance of H2C6 relative to H2 is about 4.7 x 10(-11) and that of H2C4 is about 4.1 x 10(-9). The abundance of H2C6 is in fairly good agreement with gas-phase chemical models for young molecular cloud cores, but the abundance of H2C4 is significantly larger than predicted.

[Immunochemotherapy of metastatic renal cell carcinoma with interleukin 2, interferon-alpha and 5-fluorouracil]. / Immunchemotherapie des metastasierten Nierenzellkarzinoms mit Interleukin-2, Interferon-alpha und 5-Fluorouracil.

Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) were both administered subcutaneously (SC) in combination with intravenously (IV) applied 5-fluorouracil (5-FU) for the treatment of patients with metastasized renal cell carcinoma (RCC). The therapy protocol consisted of a treatment cycle of 8 weeks, which could be carried out in an outpatient regimen. The IFN-alpha was given in each of the 8 weeks (6-9 MU/m2 once to three times weekly SC) combined sequentially with IL-2 (5-20 MU/m2 three times weekly SC for 4 weeks) and 5-FU (750 mg/m2 IV weekly for 4 weeks). Among the 30 consecutive patients treated, in 2 cases a complete, and in 9 cases a partial, remission was achieved in patients with mostly lung and skeletal metastases, with an overall objective response rate of 37%. Mean response duration was 8 months (range 3-18 months). A stable state of the disease lasting 3-18 months was observed in 10 cases. The side effects were only slight and corresponded to toxicity grade I (n = 2), grade II (n = 22) and grade III (n = 6), according to the WHO classification. In conclusion, this triple-drug biochemotherapy demonstrated significant clinical effectiveness comparable with that of an aggressive IL-2 treatment regimen (applied IV), but without its high toxicity.

[Surgical treatment of metastases in renal cell carcinoma]. / Metastasenchirurgie beim Nierenzellkarzinom.

The aim of the present study was to investigate the efficacy of surgical excision of metastases in patients with renal cell carcinoma (RCC). Eighteen patients with metastatic RCC underwent resection of metastases between 1988 and 1994 (pulmonary: n = 6; skeletal: n = 6; cerebral: n = 3; local relapse: n = 3). Two patients suffered from synchronous appearance of metastases, whereas in 16 cases a metachronous occurrence was observed. In 12 out of a total of 18 patients metastases were completely resected. These patients survived longer than patients in whom metastases were incompletely resected (30 vs. 12 months). Six out of these 12 patients with a complete resection of metastases are presently free of disease for a mean duration of 24 months (10-34 months). The resection of lung metastases seems to be associated with longer survival times. In conclusion, surgical resection of metastases--solitary or single organ site--especially in the lung appears to be justified in patients with RCC. The surgical excision of skeletal metastases at least improves quality of life.

The IRS 1 circumstellar disk, and the origin of the jet and CO outflow in B5.

We report the discovery of the inner edge of the high velocity CO outflow associated with the bipolar jet originating from IRS 1 in Barnard 5 and the first ever resolution of its circumstellar disk in the 2.6 mm dust continuum and C18O. From high spatial resolution observations made with the Owens Valley Millimeter Array we are able to locate the origin of the outflow to within approximately 500 AU on either side of IRS 1 and apparently at the edge of, or possibly within, its circumstellar disk. The orientation of the continuum disk is perpendicular to the highly collimated jet outflow recently seen in optical emission at much farther distances. The disk has been detected in C18O giving a disk mass approximately 0.16 M (solar). Our HCO+ and HCN maps indicate significant chemical differentiation in the circumstellar region on small scales with HCO+ tracing an extended disk of material. The 12CO interferometer maps of the outflow show two conelike features originating at IRS 1, the blue one fanning open to the northeast and the red one to the southwest. The vertices of the cones are on either side of the circumstellar disk and have a projected opening angle of about 90 degrees. The intrinsic opening angle is in the range of 60 degrees-90 degrees which leads to significant interaction between outflow and infall.

Evolutionary status of the pre-protostellar core L1498.

L1498 is a classic example of a dense cold pre-protostellar core. To study the evolutionary status, the structure, dynamics, and chemical properties of this core we have obtained high spatial and high spectral resolution observations of molecules tracing densities of 10(3)-10(5) cm-3. We observed CCS, NH3, C3H2, and HC7N with NASA's DSN 70 m antennas. We also present large-scale maps of C18O and 13CO observed with the AT&T 7 m antenna. For the high spatial resolution maps of selected regions within the core we used the VLA for CCS at 22 GHz, and the Owens Valley Radio Observatory (OVRO) MMA for CCS at 94 GHz and CS (2-1). The 22 GHz CCS emission marks a high-density [n(H2) > 10(4) cm -3] core, which is elongated with a major axis along the SE-NW direction. NH3 and C3H2 emissions are located inside the boundary of the CCS emission. C18O emission traces a lower density gas extending beyond the CCS boundary. Along the major axis of the dense core, CCS, NH3 and C3H2 emission show evidence of limb brightening. The observations are consistent with a chemically differentiated onion-shell structure for the L1498 core, with NH3 in the inner and CCS in the outer parts of the core. The high angular resolution (9"-12") spectral line maps obtained by combining NASA Goldstone 70 m and VLA data resolve the CCS 22 GHz emission in the southeast and northwest boundaries into arclike enhancements, supporting the picture that CCS emission originates in a shell outside the NH3 emitting region. Interferometric maps of CCS at 94 GHz and CS at 98 GHz show that their emitting regions contain several small-scale dense condensations. We suggest that the differences between the CCS, CS, C3H2, and NH3 emission are caused by a time-dependent effect as the core evolves slowly. We interpret the chemical and physical properties of L1498 in terms of a quasi-static (or slowly contracting) dense core in which the outer envelope is still growing. The growth rate of the core is determined by the density increase in the CCS shell resulting from the accretion of the outer low-density gas traced by C18O. We conclude that L1498 could become unstable to rapid collapse to form a protostar in less than 5 x 10(6) yr.

Immunochemotherapy for metastatic renal cell carcinoma using a regimen of interleukin-2, interferon-alpha and 5-fluorouracil.

PURPOSE: Promising results of recent clinical trials with a triple drug bio-chemotherapy regimen encouraged its use in patients with renal cell carcinoma. MATERIALS AND METHODS: In a phase II study of patients with metastatic renal cell carcinoma the efficacy and toxicity of a treatment regimen were evaluated using interleukin-2 and interferon-alpha 2 subcutaneously in combination with intravenous 5-fluorouracil. The treatment protocol consisted of an 8-week cycle given on an outpatient basis, with 6 to 9 MU/m2. interferon-alpha given 1 to 3 times a week during the 8 weeks, and sequentially combined with 5 to 20 MU/m2. interleukin-2, 3 times a week for 4 weeks and 750 mg./m.2 5-fluorouracil once a week for 4 weeks. RESULTS: Among 25 consecutive men and 9 women treated 3 (9%) had a complete and 10 (29%) had a partial remission (overall objective response rate 38%). Median response duration (complete plus partial) was 12.5 months (range 3 to 20+). Stable disease lasting 3 to 24+ months was noted in 12 patients (35%). There were only minor side effects, for a maximum toxicity grade of I in 3 patients, II in 25 and III in 6 according to the World Health Organization classification. There were no dose limiting toxicities and no treatment related deaths. CONCLUSIONS: Triple drug immunochemotherapy resulted in a significant clinical effect comparable to an aggressive intravenous interleukin-2 treatment regimen but without significant toxicity.

Atypical findings in a patient with a renal milk-of-calcium cyst.

A case of an atypical renal milk-of-calcium cyst is presented. Although this cyst contained a colloidal suspension of calcium crystals, other signs and findings typical for a milk-of-calcium cyst were lacking. No connection of the cyst to the collecting system could be identified, no "half moon" phenomenon was found on upright and cross-sectional radiography, and the biopsies taken from the wall of the cyst showed sclerosis instead of urothelium. From the present case it was concluded that renal milk-of-calcium cysts may sometimes occur in the absence of findings that are typical of this particular entity. Therefore, this disease should be considered in the differential diagnosis of renal calcifications of unknown origin.

Simultaneous presence of t(11;14) and a variant Burkitt's translocation in the terminal phase of a mantle cell lymphoma.

Little is known about the clinical significance of secondary chromosome aberrations in lymphomas with t(11;14)(q13;q32), the characteristic change of mantle cell lymphomas. Here we present a patient with mantle cell lymphoma, who showed a variant Burkitt's translocation t(2;8)(p12;q24) in addition to t(11;14) during the progression of the disease. An involvement of chromosome 8q24, the localization of the c-myc gene, has so far been described in only four patients, who seemed to have a fatal clinical course. Although no blastic transformation occurred in our patient, no remission could be induce by intensified treatment and survival was only 5 months. This case demonstrates that secondary chromosome aberrations can determine the clinical course of patients, even if morphologic and immunophenotypic findings fail to predict the poor outcome.